Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice (original) (raw)

The multiplicity of Notch receptors raises the question of the contribution of speci®c isoforms to T-cell development. Notch3 is expressed in CD4 ± 8 ± thymocytes and is down-regulated across the CD4 ± 8 ± to CD4 + 8 + transition, controlled by pre-T-cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter-driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4 ± 8 ± cells, a failure to down-regulate CD25 in post-CD4 ± 8 ± subsets and sustained activity of NF-kB. Subsequently, aggressive multicentric T-cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTa and activated NF-kB via IKKa-dependent degradation of IkBa and enhancement of NF-kBdependent anti-apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF-kB activation and T-cell tumorigenesis. The phenotypes of pre-malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in coordinating growth and differentiation of thymocytes, across the pre-T/T cell transition, consistent with the normal expression pattern of Notch3.

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